anti-EGFR antibody

一行要約

EGFR 細胞外ドメインに結合する mAb クラス。古典的 mAb (Cetuximab, Necitumumab, Panitumumab) と次世代 bispecific (Amivantamab = EGFR×MET) の 2 世代がある。NSCLC では Cetuximab + 化療 (FLEX), Necitumumab + 化療 (SQUIRE 扁平) が modest な OS benefit を示したが市場 impact は限定的、Amivantamab が EGFR ex20ins (CHRYSALIS) と 1L EGFR common mutation (MARIPOSA: + Lazertinib / PAPILLON: + chemo for ex20ins) で標準を更新。EGFR-TKI (small molecule) と異なり ligand binding 阻害 + receptor down-modulation + ADCC 機序を持ち、CRC では Cetuximab / Panitumumab が KRAS/NRAS WT 適応で確立済み。

メンバー比較表

薬剤	製品名	Isotype	主要 NSCLC 試験	適応
Cetuximab	Erbitux	chimeric IgG1	FLEX / SQUIRE / SWOG-S0819	化療併用、Afatinib 併用 (SWOG S1403)
Necitumumab	Portrazza	human IgG1	SQUIRE	1L 扁平 NSCLC + cisplatin+gemcitabine
Panitumumab	Vectibix	human IgG2	NSCLC 適応外 (CRC のみ)	—
Amivantamab	Rybrevant	EGFR×MET bispecific	CHRYSALIS / MARIPOSA / PAPILLON	EGFR ex20ins、1L EGFR+ + Lazertinib (→ BiTE-bispecific)

主要エビデンス

Classical anti-EGFR mAb + chemotherapy (NSCLC)

• FLEX (Pirker Lancet 2009) : Cetuximab + cisplatin+vinorelbine vs chemo 1L NSCLC、OS 11.3 vs 10.1 mo (HR 0.871、p=0.044) → modest benefit、適応取得は限定的
• SQUIRE (Thatcher et al. LancetOncol 2015) : Necitumumab + cisplatin+gemcitabine vs gemcitabine+cisplatin 1L 扁平 NSCLC、OS 11.5 vs 9.9 mo (HR 0.84、p=0.01) → FDA / EMA 承認するも商業撤退 (コスト・希少効果)
• SWOG-S0819 (Herbst et al. LancetOncol 2018) : Cetuximab + carbo+paclitaxel±Bev、ITT で OS 改善せず、EGFR FISH+ subset で OS 11.8 vs 10.0 mo → biomarker selection の概念実証だが prospective validation 不足

EGFR-TKI 併用試験

• SWOG-S1403 (Goldberg et al. JClinOncol 2020) : Afatinib + Cetuximab vs Afatinib 1L EGFR-mut、PFS 改善せず (13.4 vs 11.9 mo、HR 1.01) → 1L 併用 negative
• Cetuximab + Afatinib in T790M acquired resistance (Janjigian et al. CancerDiscov 2014) : TKI 耐性後に dual inhibition で ORR 29% — Osimertinib 登場前の rescue strategy

Amivantamab (EGFR×MET bispecific、次世代)

• CHRYSALIS (Park et al. JClinOncol 2021) : EGFR ex20ins NSCLC、platinum 既治療で ORR 40%、mPFS 8.3 mo → FDA 加速承認、ex20ins 初の標的治療
• MARIPOSA (Cho NEJM 2024) : Amivantamab + Lazertinib vs Osimertinib 1L EGFR common mutation、PFS 23.7 vs 16.6 mo (HR 0.70) → 1L EGFR-mut で Osimertinib 単剤を超える regimen 確立
• PAPILLON (Zhou NEJM 2024) : Amivantamab + carboplatin+pemetrexed vs chemo alone 1L EGFR ex20ins、PFS 11.4 vs 6.7 mo (HR 0.40) → ex20ins 1L 標準
• Pre-clinical biology (Yun et al. CancerDiscov 2020) : ex20ins では EGFR allosteric pocket が steric block されるため small-molecule TKI が無効、Amivantamab の細胞外結合 + ADCC + receptor down-modulation が代替経路

免疫学的機序 (mAb 共通)

• Cetuximab + 免疫原性細胞死 (Pozzi et al. NatMed 2016) : Cetuximab + chemo が ICD (ATP/HMGB1/calreticulin) 誘導 → 抗腫瘍免疫増強
• HLA class I upregulation (Srivastava et al. CancerImmunolRes 2015) : STAT1 経由 HLA-I 上昇が HNC での Cetuximab 効果と相関 → IO 併用の根拠
• Liver metastasis での免疫細胞浸潤 (Inoue et al. CancerSci 2017) : CRC 肝転移で Cetuximab により T 細胞・NK 細胞浸潤が増加

CRC 領域 (cross-tumor reference)

• Amivantamab CRC monotherapy (Oberstein et al. JClinOncol 2026) : OrigAMI-1 phase Ib/II、RAS/BRAF WT mCRC で Amivantamab 単剤 ORR 16% / DCR 72% → CRC 既存 anti-EGFR mAb (Cetuximab/Panitumumab) の bispecific 後継候補

メカニズム

EGFR 細胞外 IgG-like ドメイン (domain III が主要 epitope) に結合し:

1. Ligand binding 阻害: EGF / TGF-α / amphiregulin の receptor 結合 block
2. Receptor dimerization 阻害: EGFR-EGFR / EGFR-HER2 / EGFR-HER3 hetero/homo dimer の形成阻害
3. ADCC (IgG1: Cetuximab / Necitumumab) : NK / macrophage 経由の腫瘍細胞 depletion。Panitumumab (IgG2) は ADCC 弱
4. Receptor internalization / degradation: lysosomal degradation 促進 → 細胞表面 EGFR 量低下
5. Immunogenic cell death: 化療併用で ICD 誘導 → 適応免疫活性化 (Pozzi et al. NatMed 2016)

Bispecific (Amivantamab) の追加機序:

• EGFR + MET 同時 engagement → ex20ins の allosteric pocket blocking 回避
• Trogocytosis (macrophage による receptor stripping)
• 強化 ADCC + ADCP (Fc engineering)

Small molecule TKI との相違: 細胞外 vs 細胞内、ligand vs ATP-binding、ADCC 有無、IV 投与 (皮下製剤も Amivantamab で開発)、infusion reaction (Cetuximab で α-Gal IgE による重症 reaction、southeastern US で頻度高い)

Resistance: EGFR ECD 変異 (S492R for Cetuximab)、EGFR amplification、HER2/HER3 upregulation、KRAS/NRAS/BRAF 二次活性化 (CRC で確立)、MET amplification (NSCLC EGFR-TKI 耐性 + Amivantamab で標的化)

Open Questions

• EGFR-mAb の現代 1L 役割: Osimertinib / IO+chemo 時代に classical mAb (Cetuximab / Necitumumab) の役割は実質消失。Necitumumab は商用撤退、Cetuximab は NSCLC では研究的使用のみ
• MARIPOSA paradigm の最適化: Amivantamab + Lazertinib 1L の毒性負荷 (皮疹・VTE・infusion reaction) vs Osimertinib 単剤 → biomarker-driven 選択 (co-mutation、CNS mets、EGFR ex19del vs L858R) の確立
• 皮下製剤化: Amivantamab subcutaneous formulation (PALOMA-3) による infusion reaction 軽減 + 投与時間短縮
• EGFR FISH+ biomarker validation: SWOG S0819 paradigm (FISH+ subset benefit) が prospective biomarker selection に活用されず → liquid biopsy 統合の余地
• Amivantamab + IO 併用: PD-1 inhibitor との安全性 / efficacy (毒性が ADCC 機序とどう相互作用するか)
• 次世代 bispecific / trispecific: EGFR×MET 以外 (EGFR×HER3 = patritumab paradigm の多重化) の開発、ADC 化 (HER3-DXd の流れと合流)

重要論文 Top 10

1. ★★★★★ Thatcher et al. LancetOncol 2015 — SQUIRE — Necitumumab 扁平 1L
2. ★★★★★ Park et al. JClinOncol 2021 — CHRYSALIS — Amivantamab ex20ins 1st evidence
3. ★★★★ Herbst et al. LancetOncol 2018 — SWOG S0819 — EGFR FISH+ biomarker subset
4. ★★★ Goldberg et al. JClinOncol 2020 — SWOG S1403 — Afatinib + Cetuximab 1L 陰性
5. ★★★★ Yun et al. CancerDiscov 2020 — Amivantamab pre-clinical biology — bispecific 機序

関連エンティティ

• 関連遺伝子: EGFR
• 関連 class: EGFR-TKI (細胞内 vs 細胞外), BiTE-bispecific (Amivantamab), ADC (Patritumab deruxtecan HER3)
• 試験: FLEX / SQUIRE / SWOG-S0819 / SWOG-S1403
• ドメイン: lung-cancer-treatment

関連論文

直近 30 件のみ表示中 (関連 151 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Brain metastasis

• Mavrikios et al. AnnOncol 2026 — Lung cancer brain metastases management at the dawn of personalized medicine are we ready to break the barriers

Basic-Extracellular vesicles

• Kalluri et al. Cell 2023 — The role of extracellular vesicles in cancer
• Cai et al. MolCancer 2026 — Extracellular vesicles in solid tumors from tumor ecology to engineered therapeutics

Basic-Liquid-biopsy

• Sinicrope et al. JClinOncol 2026 — Tissue-free circulating tumor DNA assay and patient outcome in a phase III trial of FOLFOX-based adjuvant chemotherap…

Basic-Neutrophil and myeloid cell

• Redavid et al. JImmunotherCancer 2026 — Targeting macrophage-driven NK cell immunosuppression to improve cancer immunotherapy

Basic-Oncogene and genetics

• Johnson et al. CancerDiscov 2022 — Classification of KRAS-activating mutations and the implications for therapeutic intervention

Basic-Others

• Jiang et al. Cancers 2026 — Selective inhibition of KRASG13C reveals an increased dependence on wild-type RAS
• Oberstein et al. JClinOncol 2026 — Amivantamab monotherapy in chemorefractory RASBRAF wild-type metastatic colorectal cancer results from OrigAMI-1, an
• Lu et al. Nature 2026 — Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer
• Chen et al. iScience 2024 — Translating CD47-targeted therapy in gastrointestinal cancers insights from preclinical to clinical studies

Basic-Tumor microenvironment

• Lu et al. NatBiotechnol 2026 — Single-cell spatial pharmacobiology identifies conserved stromal barriers to therapeutic antibody delivery in human

Clinical-Methodology

• Bruno et al. BrJCancer 2023 — Support to early clinical decisions in drug development and personalised medicine with checkpoint inhibitors using

Clinical-NSCLC-Driver-Other

• Kropf-Sanchen et al. ClinLungCancer 2026 — A retrospective, multicenter analysis within the national network genomic medicine lung cancer in germany to detect RET
• Canaslan et al. CritRevOncolHematol 2026 — From G12C to pan-RAS the expanding therapeutic landscape of KRAS-mutant NSCLC
• Vitale et al. CritRevOncolHematol 2026 — Targeting KRAS G12C in non-small cell lung cancer breakthrough inhibitors and combination approaches
• Zeissig et al. TrendsCancer 2023 — Next batter up! targeting cancers with KRAS-G12D mutations

Clinical-NSCLC-EGFR

• Passiglia et al. Cancer 2026 — Amivantamab in advanced non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations
• Kim et al. FrontOncol 2026 — Paired ctDNA analysis reveals diverse resistance mechanisms to mobocertinib in EGFR exon 20 insertion NSCLC
• HARMONi et al. JAMA 2026 — A-Bispecific antibody ivonescimab added to chemotherapy in EGFR-variant non-small cell lung cancer the HARMONi-A
• Li et al. LancetOncol 2026 — Aumolertinib with or without chemotherapy in EGFR-mutated advanced non-small-cell lung cancer (AENEAS2) an open-label,
• Wang et al. LungCancer 2026 — Vebreltinib plus EGFR-TKI for EGFR-mutated NSCLC with MET-driven resistance A real-world study of chinese patients
• Zhou et al. NEnglJMed 2023 — Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions
• Cho et al. NEnglJMed 2024 — Amivantamab plus lazertinib in previously untreated EGFR-Mutated advanced NSCLC
• Yang et al. NEnglJMed 2025 — Overall survival with amivantamab-lazertinib in EGFR-Mutated advanced NSCLC
• Janne et al. NEnglJMed 2026 — Survival with osimertinib plus chemotherapy in EGFR-mutated advanced nsclc
• Zhou et al. NEnglJMed 2026 — First-line sunvozertinib in NSCLC with
• Zhao et al. NatRevClinOncol 2026 — Navigating the landscape of EGFR TKI resistance in EGFR-mutant NSCLC-mechanisms and evolving treatment approaches

Clinical-Novel modalities

• Horowitz et al. SciTranslMed 2026 — Cd39+cd49a+cd103+ cytotoxic tissue-resident natural killer cells infiltrate and control solid epithelial tumor growth
• High et al. TrendsCancer 2026 — Lgr5 from stem cell marker to therapeutic target

Clinical-Others

• Mahmud et al. Oncologist 2026 — Biomarker testing patterns among patients newly diagnosed with metastatic non-small cell lung prostate and bladder ca…